Autism (autistic disorder) is a pervasive developmental disorder with diagnostic criteria based on abnormal social interactions, language abnormalities, and stereotypies evident prior to 36 months of age. Despite its lack of Mendelian transmission autism is highly genetically determined.
In most cases in which a gene has been associated with a disorder, the disease allele acts in the affected individual. Alternatively, a disease allele of a gene may act in the mother during pregnancy to contribute to the phenotype of her affected child1. So far, there is evidence for such maternally acting alleles, so-called teratogenic alleles, for only a handful of genes (reviewed in Johnson W G, 20032).
Examples of teratogenic alleles include: (1) in spina bifida, the G-allele of the MTR A2756G, the G-allele of the MTRR polymorphisms3 and the deletion allele of the DHFR 19 bp deletion polymorphism4; (2) in Down syndrome, the G-allele of the MTRR A66G and T-allele of the MTHFR C677T polymorphisms5; (3) in orofacial clefting, the GSTT1-null allele homozygotes6. Demonstrating increased frequency of a putative teratogenic allele in mothers but not fathers of affected individuals is evidence for a teratogenic allele and is the method that has been used in most reports. Strong evidence of a teratogenic allele, e.g. by maternal transmission disequilibrium testing (TDT) has rarely been achieved3, and there is strong evidence for none so far in autism.
Children with autistic disorder (AD) show deviation from the normal developmental pattern with impaired social interactions and communication, restricted interests, and repetitive, stereotyped patterns of behaviour that are evident prior to 36 months of age7,8. Clinical genetic studies and modelling studies suggest that AD may be caused by multiple interacting gene loci9,10 while environmental and epigenetic factors may contribute to variable expressivity possibly through interaction with genetic susceptibility factors10,11. Environmental factors contributing to AD could include toxic endogenous metabolites or exogenous toxins or teratogens.
Neuropathological studies12,13, cytoarchitectonic studies14, minicolumn studies15,16 and neonatal blood studies of neurotrophins and neuropeptides17 all support the prenatal origin of certain brain abnormalities in autism. Consequently, it is possible that maternal genes, acting during pregnancy, could contribute to the autism phenotype in the fetus.
A number of maternal effects have been described for autism, but none reported so far gives strong evidence of a teratogenic allele. For some of these no involvement of specific maternal genes have yet been demonstrated, e.g., autism associated with maternal ingestion during pregnancy of thalidomide18 or valproic acid19 and increased risk of autism spectrum disorder in children of mothers with diabetes or epilepsy20. There is some evidence that maternal alleles at the MAO-A locus and possibly the DBH locus may modify IQ in children with autism21. Diminished IQ is often seen in autism, though not as a cardinal feature. Although mental retardation is not part of the diagnostic criteria for autism, the two diagnoses could be interacting through diagnostic substitution in the population22. In addition, some alleles of the glutamate receptor 6 (GluR6, GRIK2) reportedly showed increased maternal transmission to male children with autism23; these findings were ascribed to meiotic drive or imprinting. There is evidence that the major histocompatibility complex (MHC) extended haplotype, HLA B44-SC30-DR4, may act as a teratogenic allele for autism since the frequency of this haplotype was increased in mothers of autism cases compared with controls24. So far, this has not been confirmed with a stronger study design such as maternal TDT. This haplotype frequency was also increased in autism cases compared with controls suggesting action in the cases as well24.
Some recent studies in humans have linked oxidative stress to autism25. For example, significantly decreased levels of glutathione (GSH), significantly lower ratio of reduced GSH to oxidized GSH, and other metabolic abnormalities in individuals with autism were interpreted as evidence of oxidative stress26,27. Glutathione is the most important endogenous antioxidant28 and is the most abundant non-protein thiol29. Recently, increased urinary excretion of 8-isoprostane-F2α, a biomarker of lipid peroxidation and oxidative stress, was found in autism30, a finding that has been confirmed31.
Accumulating data support the importance of the glutathione S-transferase (GST) supergene family as one of the factors protecting against reactive oxygen species and the products of oxidative stress32,33. GSTs, one category of Phase II enzymes34, catalyze the conjugation of GSH to a variety of toxic electrophiles that have been activated by phase I enzymes. GSTs conjugate and detoxify products of oxidative stress. GSTs also conjugate toxins that produce oxidative stress35. Sometimes, conjugation of GSH to a compound by GST can increase its toxicity or even create toxicity36.
Seven cytosolic families of GSTs are known in humans, including at least 16 cytosolic GST subunits (most of them polymorphic), with some alleles causing functional alteration. For alleles with diminished function, their specific substrates might accumulate and contribute to oxidative damage; increased enzyme activity could also lead to oxidative damage; increased enzyme activity could also lead to oxidative damage if the product is toxic.35 The pi class of GSTs, represented by a single GST (variously known as GSTP1, GSTP1-1. GSTP, GSTp, and GSTpi) coded for by a gene on chromosome 11q13, is expressed at the highest levels in most extrahepatic tissues.36 
GSTP1 has 4 recognized polymorphic alleles, designated *A, *B, *C, and *D. These alleles result from 2 amino acid changes: Ile105Val (A313G) and Ala114Val (C341T). There is evidence37,38 that these polymorphic variants are functional, affecting enzyme activity and substrate specificity. For example, variation at position 105 affects thermostability of the GSTP1 enzyme39 and its catalytic efficiency for some substrates39,40 and correlates with oxidative DNA damage in breast cancer tissues.41 
There remains a need for methods and assays to determine susceptibility to and provide diagnostic markers associated with autism. Improved methods and additional relevant autism genetic markers are therefore needed. Further, identification of relevant and novel targets for intervention and therapy to prevent, alleviate, and modulate autism is needed.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.